Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection

Objectives: We investigated JNJ-64530440 (a hepatitis B virus capsid assembly modulator) safety, antiviral activity and pharmacokinetics in patients with chronic hepatitis B (CHB).
Methods: Twenty treatment-naive, HBeAg-positive or -negative CHB patients were randomized 4‍:‍1 to JNJ-64530440 750 mg once or twice daily, or placebo for 28 days.
Results: All patients (mean age 43.8 years; 85% male; 70% White; 20% HBeAg positive) completed dosing/28 day follow-up. Mild-to-moderate treatment-emergent adverse events occurred in 3/4 (placebo), 6/8 (once-daily) and 4/8 (twice-daily) patients; mostly fatigue, increased alanine aminotransferase, decreased neutrophil count, and headache. Hepatitis B virus (HBV) DNA was substantially reduced; mean (range) changes from baseline at day 29 were: -3.2 (-2.4 to -3.9) (once-daily) and -3.3 (-2.6 to -4.1) (twice-daily) log10 IU/mL; placebo 0.1 (0.7 to -0.6) log10 IU/mL. HBV DNA levels were below the lower limit of quantification (LLOQ) in 5/8 (once-daily) and 3/8 (twice-daily) patients. For patients with detectable baseline HBV RNA, mean (SE) changes versus baseline in HBV RNA at day 29 were: -2.65 (0.81) (once-daily) and -2.94 (0.33) (twice-daily) log10 copies/mL. HBV RNA levels were ‘target not detected’ in 4/6 (once-daily) and 3/7 (twice-daily) patients. JNJ-64530440 pharmacokinetics in CHB patients were comparable with those in healthy volunteers.

Amivantamab (JNJ-61186372) induces clinical, biochemical, molecular, and radiographic response in a treatment-refractory NSCLC patient harboring amplified triple EGFR mutations (L858R/ T790M/G796S) in cis

  • The sequential use of 1st-/2nd-generation to 3rd-generation epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) has led to the emergence of triple EGFR mutations generally consisting of the founder mutation (del 19 or L858R), gatekeeper mutation (T790M) and mutation (C797S) that abolishes the covalent binding of osimertinib to the EGFR protein (i.e., del 19 or L858R/T790M/C797S).
  • Besides C797S, other tertiary mutations confer structural steric hindrance to osimertinib rather than preventing its covalent binding to the EGFR kinase domain such as solvent front mutation (G796S) or others such as L792F/H mutation. “Fourth-generation” EGFR TKIs are being developed to inhibit these triple mutations, in particular, in the background of compound T790M/C797S mutations but they are still in early clinical stages of development.
  • Amivantamab, a bi-specific EGFR/MET monoclonal antibody that can affect Fc mediated trogocytosis of the EGFR protein has been approved for the treatment of EGFR exon20 insertion mutations and has demonstrated activity against a myriad of compound EGFR mutations.Here we report amivantamab monotherapy induced symptomatic, biochemical, molecular, and radiographic responses in a NSCLC patient with triple EGFR mutations in cis in the background of EGFR amplification.

Spotlight on Amivantamab (JNJ-61186372) for EGFR Exon 20 Insertions Positive Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) patients demonstrating sensitizing oncogenic driver mutations have derived clinical benefit from targeted therapy. EGFR mutations constitutively activate the signaling pathway, leading to prosurvival and antiapoptotic signals. Classic sensitizing EGFR mutations, such as exon 19 deletions and exon 21 L858R point mutations, respond well to tyrosine kinase inhibitors (TKIs).
On the other hand, EGFR exon 20 in-frame insertions are observed in 4-12% of EGFR-mutated NSCLC and are resistant to targeted therapy with TKIs. In May 2021, the Federal Drug Administration (FDA) provided accelerated approval to amivantamab (Rybrevant) in adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations after treatment with platinum-based chemotherapy. Here, we discuss properties of amivantamab, clinical trial results, and management of patients with EGFR exon 20 insertion mutated NSCLC.

Treatment with the Prolyl Hydroxylase Inhibitor JNJ Promotes Abdominal Aortic Aneurysm Progression in Diabetic Mice

Objective: Prolyl hydroxylase domain containing proteins (PHD) rigorously regulate intracellular hypoxia inducible factor-1 (HIF-1) protein expression and activity. Diabetes impairs PHD activity and attenuates abdominal aortic aneurysm (AAA) progression. The extent to which dysregulated PHD activity contributes to diabetes mediated AAA suppression remains undetermined.
Methods: AAAs were induced in diabetic and non-diabetic male C57BL/6J mice via intra-aortic elastase infusion. A PHD inhibitor (JNJ-42041935, aka “JNJ”, 150 mmol/kg) or vehicle alone was administered daily starting one day prior to AAA induction for 14 days. Influences on AAA progression was assessed via ultrasonography and histopathology. Expression of aortic HIF-1α, three of its target genes and macrophage derived mediators were assayed via quantitative reverse transcription polymerase chain reaction. Aneurysmal sections from AAA patients with and without diabetes (two patients in each group) were immunostained for HIF-1α and vascular endothelial growth factor (VEGF)-A.
Results: Expression of HIF-1α target genes (erythropoietin, VEGF-A, and glucose transporter-1) was reduced by 45% – 95% in experimental diabetic aortas. Diameter enlargement was similarly limited, as were mural elastin degradation, leukocyte infiltration, and neo-angiogenesis (reduced capillary density and length) on histopathology. Pre-treatment with JNJ prior to AAA initiation augmented aortic HIF-1α target gene expression and aneurysm progression in diabetic mice, along with macrophage VEGF-A and matrix metalloproteinase 2 mRNA expression. No differences were noted in HIF-1α or VEGF-A expression on aortic immunohistochemical staining of human aortic tissue as a function of diabetes status.
Conclusion: Small molecule PHD inhibitor treatment reduces or offsets impairment of experimental AAA progression in hyperglycemic mice, highlighting the potential contribution of dysregulated PHD activity to diabetes mediated aneurysm suppression.

JNJ-31020028

HY-14450 MedChemExpress 100mg 911 EUR

JNJ-40411813

HY-15748 MedChemExpress 50mg 3080 EUR

JNJ-42153605

HY-18162 MedChemExpress 100mg 1359 EUR

JNJ-46778212

HY-19559 MedChemExpress 5mg 187 EUR

JNJ-42165279

HY-19636 MedChemExpress 100mg 1413 EUR

JNJ-63533054

HY-19838 MedChemExpress 50mg 628 EUR

JNJ-18038683

HY-19889 MedChemExpress 1mg 223 EUR

JNJ-38877605

HY-50683 MedChemExpress 5mg 195 EUR

JNJ-10229570

HY-107139 MedChemExpress 10mM/1mL 492 EUR

JNJ-38877618

HY-111050 MedChemExpress 10mg 405 EUR

JNJ-61432059

HY-111751 MedChemExpress 5mg 567 EUR

JNJ-678

HY-112180 MedChemExpress 10mM/1mL 620 EUR

JNJ-632

HY-112564 MedChemExpress 100mg 940 EUR

JNJ-54175446

HY-117508 MedChemExpress 1mg 681 EUR

JNJ-5207852

HY-12190 MedChemExpress 5mg 153 EUR

JNJ-42041935

HY-12832 MedChemExpress 10mM/1mL 231 EUR

JNJ-7777120

HY-13508 MedChemExpress 10mM/1mL 148 EUR

JNJ-17203212

HY-100129 MedChemExpress 50mg 766 EUR

JNJ-39758979

HY-101189 MedChemExpress 100mg 2943 EUR

JNJ-64619178

HY-101564 MedChemExpress 5mg 302 EUR

JNJ-7706621

HY-10329 MedChemExpress 2mg 131 EUR

JNJ-​10198409

HY-W011266 MedChemExpress 5mg 394 EUR

JNJ-26481585

E1KS1096 EnoGene 5mg 874 EUR

JNJ-38877605

E1KS1114 EnoGene 2mg1​ PHYSICAL AND CHEMICAL PROPERTIES 325 EUR

JNJ 26854165

E1KS1172 EnoGene 5mg 443 EUR

JNJ-7706621

E1KS1249 EnoGene 2mg 521 EUR

JNJ-42165279

C4122-10 ApexBio 10 mg 342 EUR

JNJ-42165279

C4122-25 ApexBio 25 mg 598 EUR

JNJ-64794964 (AL-034/TQ-A3334), a TLR7 agonist, induces sustained anti-HBV activity in AAV/HBV mice via non-cytolytic mechanisms

JNJ-64794964 (JNJ-4964/AL-034/TQ-A3334), an oral toll-like receptor 7 agonist, is being investigated for the treatment of chronic hepatitis B (CHB), a condition with a high unmet medical need. The anti-hepatitis B (HBV) activity of JNJ-4964 was assessed preclinically in an adeno-associated virus vector expressing HBV (AAV/HBV) mouse model. Mice were treated orally with 2, 6 or 20 mg/kg of JNJ-4964 once-per-week for 12 weeks and then followed up for 4 weeks. At 6 mg/kg, a partial decrease in plasma HBV-DNA and plasma hepatitis B surface antigen (HBsAg) were observed, and anti-HBs antibodies and HBsAg-specific T cells were observed in 1/8 animals. At 20 mg/kg, plasma HBV-DNA and HBsAg levels were undetectable for all animals 3 weeks after start of treatment, with no rebound observed 4 weeks after JNJ-4964 treatment was stopped. .
High anti-HBs antibody levels were observed until 4 weeks after JNJ-4964 treatment was stopped. In parallel, HBsAg-specific immunoglobulin G-producing B cells and interferon-γ-producing CD4+ T cells were detected in the spleen. In 2/4 animals, liver HBV-DNA and HBV-RNA levels, and liver hepatitis B core antigen expression dropped 4 weeks after JNJ-4964 treatment-stop. In these animals, HBsAg-specific CD8+ T cells were detectable. Throughout the study, normal levels of alanine aminotransferase were observed, with no hepatocyte cell death (end of treatment and 4 weeks later) and minimal infiltrations of B and T cells into the liver, suggesting induction of cytokine-mediated, non-cytolytic mechanisms.

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